HIV-associated adipose redistribution syndrome (HARS), a form of lipodystrophy, is a common problem in HIV patients on highly active antiretroviral therapy and occurs as a side-effect of their anti-viral drug therapies. HARS is characterized by an increase in visceral adipose tissue, dyslipidemia, and insulin insensitivity, all of which are believed to increase the patient's risk for developing cardiovascular disease. Recombinant GH is effective at treating HARS, as measured by reductions in visceral adipose tissue and improvement in lipid profiles. Recombinant GH products had worldwide sales of $2.4 billion in 2006, primarily from sales of the drug to treat GH deficiency in children and adults. GH has a short circulating half-life and must be administered to patients by daily injection. We created a highly potent, long-acting GH analog, BBT-031 that has a significantly increased circulating half-life and superior efficacy in animal models of growth hormone deficiency compared to GH. Based upon animal studies we anticipate that our long- acting GH analog will be effective when administered once per week or less frequently in humans. The improved in vivo characteristics of this novel GH analog will reduce the need for frequent injections, improve patient quality of life and potentially lead to a more effective therapy for the treatment of HARS. Our long-acting GH analog has the potential to significantly reduce healthcare costs by reducing the amount of drug required by patients, by reducing costs associated with patient visits to treatment centers and by reducing healthcare worker time associated with providing treatments. The overall goal of this SBIR proposal is to develop this long-acting GH analog for the treatment of HARS and other metabolic complications of HIV and HIV therapies such as wasting (cachexia). During Phase I of the SBIR grant, we developed a GLP (Good Laboratory Practices) manufacturing process and supporting assay methods to produce material for GLP pharmacology and toxicology studies. We performed single injection and repeat injection GLP toxicology studies in rats and a GLP pharmacokinetic study in rats. No toxicities were noted at doses up to 30 times the expected dose to be used in humans, and the pharmacokinetic profile of the protein suggested it will be effective as a once weekly therapy in humans. We also showed that the protein was more potent than GH at stimulating weight gain and bone growth in growth hormone deficient rats, particularly when using a less frequent dosing regimen. During Phase I we also designed clinical protocols for Phase 1 safety and Phase 2 dose ranging efficacy studies in humans. The main goal of the Phase II SBIR proposal is to complete animal toxicology and pharmacology studies in a second species, which is required by the FDA prior to testing this product in humans. We also will continue to optimize the manufacturing process and analytical assays for the protein and perform experiments to identify a stable liquid formulation for the protein for use in humans. Successful development of our long-acting GH analog will provide HARS patients with a more convenient and potentially more effective treatment for their disease. This product also has potential for treating HIV-associated wasting (cachexia), for which GH has received approval by the FDA. Although not as significant a problem in U.S. due to wider use of more effective antiviral therapies, HIV-associated wasting still is a major problem in undeveloped countries where patients do not have as good access to HIV medications. PUBLIC HEALTH RELEVANCE HIV-associated adipose redistribution syndrome (HARS) occurs as a side-effect of highly active antiretroviral therapy (HAART) and is believed to afflict approximately 80,000 HIV patients in the U.S. HARS is characterized by an accumulation of visceral adipose tissue and alterations in lipid profiles. Recombinant growth hormone (GH), which is widely used to treat growth hormone deficiency in children and adults, has been shown to benefit HIV patients with HARS by reducing visceral adipose tissue and improving lipid profiles. A limitation of current GH therapies is the fact that they must be administered to patients by daily injection due to the short half-life of GH in people. We created a longer acting and more potent GH analog, BBT-031, which may potentially provide HARS patients with a more effective therapy, reduce the amount of GH required per patient, improve patient safety, compliance and quality of life, and result in considerable cost savings to patients and healthcare providers. During the Phase I grant we developed a GLP (Good Laboratory Practices) manufacturing process for BBT-031, developed analytical assays for measuring product purity and potency, and performed short term (up to 28 days) GLP animal toxicology, pharmacokinetic and efficacy studies in rodents. No toxicities were noted at doses up to 30 times the expected dose to be used in humans. The goals of this Phase II grant proposal are to build upon these positive results by (1) performing toxicology and pharmacokinetic studies in a second animal species, which is required by the FDA prior to testing the compound in humans; (2) perform longer term toxicology studies in two animal species; (3) continue to optimize the manufacturing process and analytical assays for the protein; and (4) identify a stable liquid formulation for the protein for use in humans. [unreadable] [unreadable] [unreadable]